IntracorticalBrain-ComputerInterfaces(iBCIs)aimtorestorecommunication,mobility,and independencetoVeteransandotherswithparalyzingdisorderssuchasamyotrophiclateralsclerosis (ALS),stroke,orspinalcordinjury.InthelatestagesofALS,theprogressivelossofmobilityis accompaniedbyalossofspeech,resultingintetraplegiaandanarthria,orlocked-insyndrome. Thoughassistiveandaugmentativecommunication(AAC)devicespartiallyaddressthisproblem,such devicesbecomelessusefulandeventuallyfailasmotorpowercontinuestodecline.Incontrast,iBCIs canrecordtheneuralactivityassociatedwithintendedmovementdirectlyfromcortex.Inthisrenewal MeritReviewapplication,weproposetoexpanduponthetremendousprogressmadeinthe developmentoftheinvestigationalBrainGateNeuralInterfacesystemtowardprovidingVeteranswith intuitive,always-available,wirelesspoint-and-clickcontroloveracomputer,tablet,oranyothersoftware- basedcommunicationsystem. Intheproposedresearch,wewillrecruittwoVeteransorotherpeoplewithALSattheProvidenceVA MedicalCentertoparticipateintheongoingBrainGatepilotclinicaltrial.Afterplacementoftwo4x4x1.5 mm,96-electrdodeBlackrock(Utah)recordingarraysinthedominantmotorcortex,participantswill engageintwoorthreerecordingsessionsperweek,intheirplaceofresidence.Theresearch,whichwill alsoleverageotherparticipantsinthemulti-siteBrainGatetrial,willfocusoverayearormorewith eachparticipantonthedevelopmentofimproved,robustneuraldecoders.Asafirstaim,wewillextend thestabilityofneuralcontrolbydevelopinganewclassofrelationaldecoderswithimprovedflexibility, adaptability,andnoisetolerance.Thiswillbefacilitatedbytheuseofadiscriminativeratherthan generativedecodingapproachthatfocusesonmodelingtheprobabilitydistributionofthe(low- dimensional)volitionalstateoutputsbasedon(high-dimensional)neuralsignals.Thisstrategydoesnot relyuponanunderlyingassumptionofcosinetuningtoendpointvelocity,andallowsforflexible,non- linearmappingacrossdifferentintendedmovementsandeffectorswithincreasedtolerancetonoise.In thesecondaim,wewilldevelopnewstrategiestorapidlycalibrateandcontinuouslyupdateneural decoders.Ournewmethodologywillallowustotransitiondirectlytoclosedloopcontrolandtocalibrate functionalneuraldecoderswithin~1minuteofactivatingthesystem.Wewillalsoimplementnew strategiestomaintaincontinuouslybothintendeddirectionandclickdecodingbyupdatingthedecoder aftereverysuccessfultargetselection,ausefulsteptowardthedesignofembeddedneuroprosthetic systemsandpractical,independentuseofaniBCI.Inbothoftheseaims,decoderswillbecomparedto thecurrentstateoftheartapproachesforBCIcontrol.Finally,wewilldevelopaclosedloopsupervisor systemcapableofdetectingidlestates,automaticallyswitchingbetweendesiredeffectorsandtriggering decoderrecalibration.Theseinnovations,togetherwiththefirstuseofahigh-bandwidthwirelessneural signaltransmitterinhumaniBCIs,willresultinanautonomous,self-regulatingsystem,helpingtorestore independencetousersbyreducingtherelianceonanable-bodiedcaregiver.Thecombinationofthese innovations,rigorouslytestedbyahighlyexperiencedandtightlycollaborativeteamofclinicians, neuroscientists,andengineers,willtranslatethecurrentiBCIsystemtowardenablingindependent, intuitive,iBCI-enabledcommunicationbyVeteranswithALS.